This research program is a new attack on certain basic questions of the physiology and pathology of pancreatic islets through direct analysis of pure islet tissue: what are the metabolic events taking place in endocrine cells during increased secretory activity and what goes wrong in Beta-cells at the biochemical level during development of experimental or genetic diabetes? An attempt to tackle these problems is made by combined use of three approaches: 1) evaluation of the islets functional capacity in various nutritional, pharmacological and pathological states by analysis of insulin and glucagon release in vivo and in the isolated perfused pancreas; 2) isolation of pure individual islets from frozen-dried sections, processed with quantitative histochemical procedures combined with quick-freezing techniques, and 3) study of these islets by measurements of metabolite levels and enzyme activities as indicators of biochemical mechanisms. Chemical analysis is based on: 1) enzymatic pyridine nucleotide dependent fluorometric methods together with techniques of enzymatic cycling and an oil-well method or 2) recently greatly refined gaschromatographic procedures. It is believed this broad approach will continue to provide insight into a) the complex interrelation between intermediary metabolism of pancreatic islets and hormone release and b) the derangement of this relationship in disease.